MiR-103a-3p promotes tumour glycolysis in colorectal cancer via hippo/YAP1/HIF1A axis

Zhenqiang Sun,Guixian Wang,Qiuge Zhang,Quancheng Kan,Weitang Yuan,Qin Dang,Qisan Wang,Yaxin Guo,Chen Chen,Quanbo Zhou,Xiaoli Li,Bo Shao,Jinbo Liu

doi:10.1186/s13046-020-01705-9

Abstract

BackgroundGlycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. However, the complex regulatory mechanisms of tumour glycolysis remain elusive. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC).MethodsWe explored the effects of miR-103a-3p on glycolysis and the biological functions of CRC cells in vitro and in vivo. Furthermore, we investigated whether miR-103a-3p regulates HIF1A expression through the Hippo/YAP1 pathway, and evaluated the role of the miR-103a-3p-LATS2/SAV1-YAP1-HIF1A axis in promoting glycolysis and angiogenesis in CRC cells and contributed to invasion and metastasis of CRC cells.ResultsWe found that miR-103a-3p was highly expressed in CRC tissues and cell lines compared with matched controls and the high expression of miR-103a-3p was associated with poor patient prognosis. Under hypoxic conditions, a high level of miR-103a-3p promoted the proliferation, invasion, migration, angiogenesis and glycolysis of CRC cells. Moreover, miR-103a-3p knockdown inhibited the growth, proliferation, and glycolysis of CRC cells and promoted the Hippo-YAP1 signalling pathway in nude mice in a xenograft model. Here, we demonstrated that miR-103a-3p could directly target LATS2 and SAV1. Subsequently, we verified that TEAD1, a transcriptional coactivator of Yes-associated protein 1 (YAP1), directly bound to the HIF1A promoter region and the YAP1 and TEAD1 proteins co-regulated the expression of HIF1A, thus promoting tumour glycolysis.ConclusionsMiR-103a-3p, which is highly expressed in CRC cells, promotes HIF1A expression by targeting the core molecules LATS2 and SAV1 of the Hippo/YAP1 pathway, contributing to enhanced proliferation, invasion, migration, glycolysis and angiogenesis in CRC. Our study revealed the functional mechanisms of miR-103a-3p/YAP1/HIF1A axis in CRC glycolysis, which would provide potential intervention targets for molecular targeted therapy of CRC.

Highlights

Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years
MiR-103a-3p is an oncogene in colorectal cancer (CRC) and is correlated with poor prognosis in CRC patients To assess the role of miR-103a-3p in CRC, we first quantitated miR-103a-3p gene expression levels in CRC tissues and adjacent tissues using the microarray datasets GSE49246 and GSE115513 (P < 0.001; Fig. 1a)
Patients with high miR-103a-3p levels had a worse prognosis and shorter survival time than those with low miR-103a-3p expression. These findings suggested that miR-103a-3p may play an oncogenic role in CRC

Summary

Introduction

Glycolysis plays an essential role in the growth and metastasis of solid cancer and has received increasing attention in recent years. This study aimed to explore the molecular effect and mechanism of the noncoding RNA miR-103a-3p on glycolysis in colorectal cancer (CRC). Tumour cells have their own specific mechanism of cell metabolism, that is, a metabolic mode mainly based on glycolysis [4,5,6]. If the glycolytic pathway of CRC cells is effectively inhibited, tumour progression can be controlled. At present, there is still no obvious effective drug targeting tumour cell metabolism. Studying the specific mechanism of CRC metabolism and finding effective molecular diagnostic and treatment targets is expected to prolong the survival of patients and improve prognosis

Objectives

Methods

Results

Discussion

Conclusion